Concanamycin A counteracts HIV-1 Nef to enhance immune clearance of infected primary cells by cytotoxic T lymphocytes.

Nef is an HIV-encoded accessory protein that enhances pathogenicity by down-regulating major histocompatibility class I (MHC-I) expression to evade killing by cytotoxic T lymphocytes (CTLs). A potent Nef inhibitor that restores MHC-I is needed to promote immune-mediated clearance of HIV-infected cells. We discovered that the plecomacrolide family of natural products restored MHC-I to the surface of Nef-expressing primary cells with variable potency. Concanamycin A (CMA) counteracted Nef at subnanomolar concentrations that did not interfere with lysosomal acidification or degradation and were nontoxic in primary cell cultures. CMA specifically reversed Nef-mediated down-regulation of MHC-I, but not CD4, and cells treated with CMA showed reduced formation of the Nef:MHC-I:AP-1 complex required for MHC-I down-regulation. CMA restored expression of diverse allotypes of MHC-I in Nef-expressing cells and inhibited Nef alleles from divergent clades of HIV and simian immunodeficiency virus, including from primary patient isolates. Lastly, we found that restoration of MHC-I in HIV-infected cells was accompanied by enhanced CTL-mediated clearance of infected cells comparable to genetic deletion of Nef. Thus, we propose CMA as a lead compound for therapeutic inhibition of Nef to enhance immune-mediated clearance of HIV-infected cells.

Serial Intralesional Steroid Injection for Subglottic Stenosis: Systemic Side Effects and Impact on Surgery-Free Interval.

OBJECTIVES: In-office serial intralesional steroid injections (SILSIs) have become a commonly used treatment for subglottic stenosis. We characterized the impact of SILSIs on the time between operating room visits and incidence of glucocorticoid systemic side effects. STUDY DESIGN: Retrospective case series. SETTING: Academic tertiary care center. METHODS: All patients with subglottic stenosis receiving SILSIs at 1 institution from 2016 to 2020 were included. Surgery-free interval was compared using paired t tests. Side effect incidence was calculated with Kaplan-Meier methodology for visualization. RESULTS: Nineteen patients and 207 procedures were included. The majority of patients were White (95%) and female (95%) and had idiopathic subglottic stenosis (53%). Mean surgery-free interval for all patients was 8.7 months (95% CI, 5.6-11.8) before initiating SILSIs. Of 11 patients with calculable surgery-free interval, 10 experienced improvement, with a mean surgery-free interval increase of 4.6 months (95% CI, 2.4-6.7). Seven patients have not required surgery since initiation of SILSIs, with a mean follow-up time of 28 months (95% CI, 25-31). Noncutaneous systemic side effects occurred at a mean 3.2 months (95% CI, 2.4-4.0) from first injection and included Cushing's syndrome, increased intraocular pressure, central serous chorioretinopathy, and new insulin requirement in the setting of diabetes. CONCLUSIONS: Ninety-one percent of patients who initiated SILSIs and had a subsequent return to the operating room experienced a mean 4.6-month increase in surgery-free interval. Systemic side effects of glucocorticoids occurred in 32% of patients after initiating SILSIs. This should be considered in preprocedure counseling and side effect monitoring during treatment.

Postacute COVID-19 Laryngeal Injury and Dysfunction.

OBJECTIVE: Patients with COVID-19 are at risk for laryngeal injury and dysfunction secondary to respiratory failure, prolonged intubation, and other unique facets of this illness. Our goal is to report clinical features and treatment for patients presenting with voice, airway, and/or swallowing concerns postacute COVID-19. STUDY DESIGN: Case series. SETTING: Academic tertiary care center. METHODS: Patients presenting with laryngeal issues following recovery from COVID-19 were included after evaluation by our laryngology team. Data were collected via retrospective chart review from March 1, 2020, to April 1, 2021. This included details of the patient's COVID-19 course, initial presentation to laryngology, and subsequent treatment. RESULTS: Twenty-four patients met inclusion criteria. Twenty (83%) patients were hospitalized, and 18 required endotracheal intubation for a median (range) duration of 14 days (6-31). Ten patients underwent tracheostomy. Patients were evaluated at a median 107 days (32-215) after their positive SARS-CoV-2 test result. The most common presenting concerns were dysphonia (n = 19, 79%), dyspnea (n = 17, 71%), and dysphagia (n = 6, 25%). Vocal fold motion impairment (50%), early glottic injury (39%), subglottic/tracheal stenosis (22%), and posterior glottic stenosis (17%) were identified in patients who required endotracheal intubation. Patients who did not need intubation were most frequently treated for muscle tension dysphonia (67%). CONCLUSION: Patients may develop significant voice, airway, and/or swallowing issues postacute COVID-19. These complications are not limited to patients requiring intubation or tracheostomy. Multidisciplinary laryngology clinics will continue to play an integral role in diagnosing and treating patients with COVID-19-related laryngeal sequelae.